JPH0588236B2 - - Google Patents
Info
- Publication number
- JPH0588236B2 JPH0588236B2 JP60015109A JP1510985A JPH0588236B2 JP H0588236 B2 JPH0588236 B2 JP H0588236B2 JP 60015109 A JP60015109 A JP 60015109A JP 1510985 A JP1510985 A JP 1510985A JP H0588236 B2 JPH0588236 B2 JP H0588236B2
- Authority
- JP
- Japan
- Prior art keywords
- formula
- oxo
- compound
- ethyl
- general formula
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Lifetime
Links
- 125000000217 alkyl group Chemical group 0.000 claims description 12
- 150000003839 salts Chemical class 0.000 claims description 7
- 229910052739 hydrogen Inorganic materials 0.000 claims description 6
- 239000001257 hydrogen Substances 0.000 claims description 6
- QPFYGEHDYLCEQA-UHFFFAOYSA-N 2-amino-5-oxochromeno[2,3-b]pyridine-3-carboxylic acid Chemical class O1C2=CC=CC=C2C(=O)C2=C1N=C(N)C(C(O)=O)=C2 QPFYGEHDYLCEQA-UHFFFAOYSA-N 0.000 claims description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 3
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 3
- 238000004519 manufacturing process Methods 0.000 claims description 3
- YGABGPVRMAUKEF-UHFFFAOYSA-N O1C2=CC=CC=C2C=C2C1=NC=C(C(=O)O)C2 Chemical class O1C2=CC=CC=C2C=C2C1=NC=C(C(=O)O)C2 YGABGPVRMAUKEF-UHFFFAOYSA-N 0.000 claims 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 26
- 150000001875 compounds Chemical class 0.000 description 26
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 15
- 239000013078 crystal Substances 0.000 description 12
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 9
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 8
- -1 cyanacetic acid ester Chemical class 0.000 description 8
- 238000006243 chemical reaction Methods 0.000 description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 7
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 6
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 5
- 238000001914 filtration Methods 0.000 description 5
- 238000002844 melting Methods 0.000 description 5
- 230000008018 melting Effects 0.000 description 5
- 238000000034 method Methods 0.000 description 5
- 239000002904 solvent Substances 0.000 description 5
- NTYJJOPFIAHURM-UHFFFAOYSA-N Histamine Chemical compound NCCC1=CN=CN1 NTYJJOPFIAHURM-UHFFFAOYSA-N 0.000 description 4
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 4
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 4
- 230000003266 anti-allergic effect Effects 0.000 description 4
- 208000006673 asthma Diseases 0.000 description 4
- 239000002585 base Substances 0.000 description 4
- 125000004432 carbon atom Chemical group C* 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 150000001412 amines Chemical class 0.000 description 3
- 235000019253 formic acid Nutrition 0.000 description 3
- 238000006460 hydrolysis reaction Methods 0.000 description 3
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 3
- 238000010992 reflux Methods 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- DCTOHCCUXLBQMS-UHFFFAOYSA-N 1-undecene Chemical compound CCCCCCCCCC=C DCTOHCCUXLBQMS-UHFFFAOYSA-N 0.000 description 2
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 2
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 2
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 2
- PVNIIMVLHYAWGP-UHFFFAOYSA-N Niacin Chemical compound OC(=O)C1=CC=CN=C1 PVNIIMVLHYAWGP-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 150000007513 acids Chemical class 0.000 description 2
- 150000001298 alcohols Chemical class 0.000 description 2
- 229910052783 alkali metal Inorganic materials 0.000 description 2
- 150000008044 alkali metal hydroxides Chemical class 0.000 description 2
- 208000026935 allergic disease Diseases 0.000 description 2
- WGQKYBSKWIADBV-UHFFFAOYSA-N benzylamine Chemical compound NCC1=CC=CC=C1 WGQKYBSKWIADBV-UHFFFAOYSA-N 0.000 description 2
- HQABUPZFAYXKJW-UHFFFAOYSA-N butan-1-amine Chemical compound CCCCN HQABUPZFAYXKJW-UHFFFAOYSA-N 0.000 description 2
- 238000004440 column chromatography Methods 0.000 description 2
- JQVDAXLFBXTEQA-UHFFFAOYSA-N dibutylamine Chemical compound CCCCNCCCC JQVDAXLFBXTEQA-UHFFFAOYSA-N 0.000 description 2
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 2
- RCKMWOKWVGPNJF-UHFFFAOYSA-N diethylcarbamazine Chemical compound CCN(CC)C(=O)N1CCN(C)CC1 RCKMWOKWVGPNJF-UHFFFAOYSA-N 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 150000002148 esters Chemical class 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 229960001340 histamine Drugs 0.000 description 2
- 210000003630 histaminocyte Anatomy 0.000 description 2
- 230000003301 hydrolyzing effect Effects 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- WHQSYGRFZMUQGQ-UHFFFAOYSA-N n,n-dimethylformamide;hydrate Chemical compound O.CN(C)C=O WHQSYGRFZMUQGQ-UHFFFAOYSA-N 0.000 description 2
- PVNIIMVLHYAWGP-UHFFFAOYSA-M nicotinate Chemical compound [O-]C(=O)C1=CC=CN=C1 PVNIIMVLHYAWGP-UHFFFAOYSA-M 0.000 description 2
- 239000002244 precipitate Substances 0.000 description 2
- 230000002265 prevention Effects 0.000 description 2
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 230000035484 reaction time Effects 0.000 description 2
- 239000002195 soluble material Substances 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 2
- 229940124597 therapeutic agent Drugs 0.000 description 2
- JWZZKOKVBUJMES-UHFFFAOYSA-N (+-)-Isoprenaline Chemical compound CC(C)NCC(O)C1=CC=C(O)C(O)=C1 JWZZKOKVBUJMES-UHFFFAOYSA-N 0.000 description 1
- LXBGSDVWAMZHDD-UHFFFAOYSA-N 2-methyl-1h-imidazole Chemical compound CC1=NC=CN1 LXBGSDVWAMZHDD-UHFFFAOYSA-N 0.000 description 1
- IMVAJLIIWCJMJP-UHFFFAOYSA-N 4-oxo-6-propan-2-ylchromene-3-carbonitrile Chemical compound O1C=C(C#N)C(=O)C2=CC(C(C)C)=CC=C21 IMVAJLIIWCJMJP-UHFFFAOYSA-N 0.000 description 1
- SFWNPLLGXKJESA-UHFFFAOYSA-N 4-oxochromene-3-carbonitrile Chemical compound C1=CC=C2C(=O)C(C#N)=COC2=C1 SFWNPLLGXKJESA-UHFFFAOYSA-N 0.000 description 1
- OJYATRCBIWZSHG-UHFFFAOYSA-N 6-acetyl-4-oxochromene-3-carbonitrile Chemical compound O1C=C(C#N)C(=O)C2=CC(C(=O)C)=CC=C21 OJYATRCBIWZSHG-UHFFFAOYSA-N 0.000 description 1
- 208000035285 Allergic Seasonal Rhinitis Diseases 0.000 description 1
- 206010012434 Dermatitis allergic Diseases 0.000 description 1
- LELOWRISYMNNSU-UHFFFAOYSA-N Hydrocyanic acid Natural products N#C LELOWRISYMNNSU-UHFFFAOYSA-N 0.000 description 1
- MKXZASYAUGDDCJ-SZMVWBNQSA-N LSM-2525 Chemical compound C1CCC[C@H]2[C@@]3([H])N(C)CC[C@]21C1=CC(OC)=CC=C1C3 MKXZASYAUGDDCJ-SZMVWBNQSA-N 0.000 description 1
- HTLZVHNRZJPSMI-UHFFFAOYSA-N N-ethylpiperidine Chemical compound CCN1CCCCC1 HTLZVHNRZJPSMI-UHFFFAOYSA-N 0.000 description 1
- 241000277284 Salvelinus fontinalis Species 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 125000003668 acetyloxy group Chemical group [H]C([H])([H])C(=O)O[*] 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 125000004423 acyloxy group Chemical group 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 229910001854 alkali hydroxide Inorganic materials 0.000 description 1
- 201000009961 allergic asthma Diseases 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 150000003863 ammonium salts Chemical class 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 1
- 201000008937 atopic dermatitis Diseases 0.000 description 1
- 208000010668 atopic eczema Diseases 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 125000004093 cyano group Chemical group *C#N 0.000 description 1
- 229960001985 dextromethorphan Drugs 0.000 description 1
- 229960003974 diethylcarbamazine Drugs 0.000 description 1
- WEHWNAOGRSTTBQ-UHFFFAOYSA-N dipropylamine Chemical compound CCCNCCC WEHWNAOGRSTTBQ-UHFFFAOYSA-N 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- ZIUSEGSNTOUIPT-UHFFFAOYSA-N ethyl 2-cyanoacetate Chemical compound CCOC(=O)CC#N ZIUSEGSNTOUIPT-UHFFFAOYSA-N 0.000 description 1
- IUDRDUQXPONSHB-UHFFFAOYSA-N ethyl 7-acetyl-2-amino-5-oxochromeno[2,3-b]pyridine-3-carboxylate Chemical compound O1C2=CC=C(C(C)=O)C=C2C(=O)C2=C1N=C(N)C(C(=O)OCC)=C2 IUDRDUQXPONSHB-UHFFFAOYSA-N 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 208000030603 inherited susceptibility to asthma Diseases 0.000 description 1
- 239000002198 insoluble material Substances 0.000 description 1
- 229940039009 isoproterenol Drugs 0.000 description 1
- 210000003097 mucus Anatomy 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 235000001968 nicotinic acid Nutrition 0.000 description 1
- 239000011664 nicotinic acid Substances 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 230000003449 preventive effect Effects 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 230000000069 prophylactic effect Effects 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 150000003335 secondary amines Chemical class 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 210000002460 smooth muscle Anatomy 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 150000003512 tertiary amines Chemical class 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 239000002699 waste material Substances 0.000 description 1
Description
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Industrial Application Field The present invention is directed to 2-amino-5-oxo-5H-, which has the effect of suppressing the release of histamine, etc., and has an antiallergic effect useful for the prevention and treatment of asthma, etc.
[1] Benzopyrano[2,3-b]pyridine-3
-Regarding a carboxylic acid derivative or a method for producing the same. BACKGROUND ART Bronchial asthma attacks are caused by the release of chemical mediators such as histamine from mast cells, base globules, etc. due to antigen-antibody reactions, which constrict bronchial smooth muscles and increase mucus secretion. It is considered. So far, there have been documents regarding 2-amino-5-oxo-5H-[1]benzopyrano[2,3-b]pyridine-3-carboxylic acid derivatives that have the effect of suppressing the release of chemical mediators from mast cells, etc. is published in Japanese Unexamined Patent Publication No. 1973
Publication No. 111096 is mentioned. Problems to be Solved by the Invention However, with respect to the compound described in JP-A-53-111096, it has been desired to further enhance the action, reduce toxicity, or increase water solubility. Means for Solving the Problems The present inventors completed the present invention as a result of conducting research to find a compound that meets the above-mentioned objectives. The present invention is based on the general formula ()
ãåŒã ãåŒäžãã¯æ°ŽçŽ ãŸãã¯äœçŽã¢ã«ãã«ããã¯ãformulaã [In the formula, R is hydrogen or lower alkyl, and A is
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ãŸãã¯ãã®å¡©ãããã³äžè¬åŒïŒïŒ[Formula] (R 1 represents hydrogen or lower alkyl) or -CO- respectively] 2-amino-5-oxo-5H-[1]benzopyrano[2,3-b]pyridine-3- Carboxylic acid derivatives or salts thereof, and general formula ()
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æ¬çºæã®äžè¬åŒååç©ïŒïŒã¯ãäžè¬åŒïŒïŒ[Formula] [In the formula, R and A have the same meanings as above,
R 2 represents lower alkyl] is a method for producing a compound represented by the general formula () or a salt thereof, which is characterized by subjecting the compound represented by the formula (2) to a hydrolysis reaction. In the above formula, the substitution position of the substituent R-X- is 6,
Any of the 7th, 8th, and 9th positions may be used; R, R 1 and
Lower alkyl represented by R 2 includes methyl,
Examples include alkyl having 1 to 6 carbon atoms such as ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, among which R has 1 to 5 carbon atoms.
Practically preferred is an alkyl group having 1 to 2 carbon atoms for R 1 and an alkyl group having 1 to 3 carbon atoms for R 2 . The compound of the general formula () of the present invention has the general formula ()
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ã®ååç©ã«ãããŠãââã[Formula] [In the formula, R and A represent the same meanings as above. ]
It can be produced by hydrolyzing a compound of the general formula () obtained by reacting the compound represented by the above with cyanacetic acid ester. Examples of the cyanacetic ester that is a raw material for producing compound () include methyl, ethyl, propyl, and butyl esters. The amount of these cyanacetic esters to be used is usually about 1 to 10 times the mole of the compound () in practice. In the above reaction, the presence of a base is generally desirable, and the base used is organic amines, for example n
-Primary amines such as butylamine, benzylamine, aniline, secondary amines such as diethylamine, dipropylamine, dibutylamine, piperidine, pyrrolidine, morpholine, 1,8-diazabicyclo[5,4,0]-7- Examples include tertiary amines such as undecene and triethylamine, and heterocyclic bases such as imidazole and 2-methylimidazole. The amount of these organic salters used is usually catalytic amount to 5 to 1 mole of compound ().
It is about double the mole. It is generally preferable to carry out the reaction in an organic solvent, and examples of the solvent include alcohols such as methanol, ethanol, propanol and butanol, aromatic hydrocarbons such as benzene and toluene, and dimethylformamide.
Other reaction conditions such as reaction temperature and reaction time are not particularly limited, but the reaction is generally carried out at room temperature to around the boiling point of the solvent used for about 1 hour to 24 hours. By hydrolyzing the compound () obtained as described above, a compound represented by the general formula () is obtained. Hydrolysis is carried out under alkaline or acidic conditions, and the alkalis used include, for example, sodium hydroxide, potassium hydroxide, etc., and the acids used include sulfuric acid, hydrochloric acid, phosphoric acid, etc. The reaction is usually carried out by heating at around 50-150°C with alcohols such as methanol, ethanol, and propanol, or organic acids such as formic acid and acetic acid. The amount of these alkali hydroxides or acids used is 1 to 100 mol per 1 mol of the compound (), and the reaction time is usually about 1 hour to several days. The compound () is, for example, ethanolamine,
dl-methylefedrin, 1-(3,5-dihydroxyphenyel)-L-isopropylaminoethanol, isoproterenol, dextromethorphan, hetrazan (diethylcarbamazine),
Organic amines such as diethylamine and triethylamine, or alkali metal hydroxides such as sodium hydroxide and potassium hydroxide, or ammonia, and the compound () are mixed in an appropriate solvent and heated, for example, by a method known per se. By reacting according to the method, an organic amine salt, alkali metal salt or ammonium salt corresponding to the compound () can be obtained. In addition, the general formula (), which is one of the raw materials of the present invention,
In the compound, R-A- is
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ã«æºããŠè£œé ãããäžè¬åŒïŒïŒ[Formula] Compounds having the general formula () are known from Japanese Patent Application Publication No. 103578/1983 or can be produced according to the method described in the publication.
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âCOâã§ããååç©ã¯ãââã[Formula] [In the formula, R and R 1 represent the same meanings as above. ] It can be produced by reacting the compound shown with N-bromosuccinimide and then reacting it with an aqueous alkali solution. In addition, compounds where R-A- is R-CO-, R-A- is R-CO-.
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Med.Chem.22ïŒ290ïŒ1979ïŒã«èšèŒã®æ¹æ³ã«æºã
ãŠè£œé ã§ãããããªãã¡äžè¬åŒïŒïŒThe compound represented by the formula can be produced according to the method described in Japanese Patent Publication No. 58-54150. On the other hand, if R-A- is -CHO, J.
It can be produced according to the method described in Med.Chem.22, 290 (1979). That is, the general formula ()
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ããšã«ãããäžè¬åŒïŒïŒ[Formula] [In the formula, R 3 represents a lower acyloxy group such as acetoxy or propionyloxy] By reacting the compound represented by cyanacetic acid ester, the general formula ()
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ããåæ¯çã®äºé²ãæ²»çã«çšããããšãã§ãããIt can be produced by obtaining a compound represented by the formula [wherein R 3 has the same meaning as defined above] and subjecting it to a mild hydrolysis reaction using dilute hydrochloric acid or the like. Effect The compounds thus produced () or their salts have anti-allergic effects, and among them, salts with specific organic amines as mentioned above exhibit particularly excellent anti-allergic effects.
For example, it is useful as a preventive or therapeutic agent for allergic diseases such as allergic asthma, allergic dermatitis, and hay fever. Furthermore, these alkali metal salts and organic amine salts have good solubility in water,
In addition, their aqueous solutions are stable and convenient for formulation into injections, solutions, and the like. When the compound () or its salts are used, for example, as a prophylactic or therapeutic agent for the above-mentioned allergic diseases, the adult dose is usually about 1 to 500 mg/day, which is orally administered in the form of tablets, capsules, powders, solutions, etc. It can be administered in an appropriate dosage form such as an injection, an inhaler spray, or an ointment. EXAMPLES The present invention will be explained in more detail by referring to Reference Examples and Examples below. Reference example 1 6-isopropyl-4-oxo-4H-1-benzopyran-3-carbonitrile (10.65 g) was suspended in carbon tetrachloride (300 ml), N-bromosuccinimide (8.90 g) was added, and an infrared lamp was added. (Toshiba,
After heating under reflux for 2 hours under irradiation (100 V, 375 WR), the mixture was cooled to room temperature and insoluble materials were filtered off. The filtrate was concentrated under reduced pressure, the residue was dissolved in ethyl acetate (150 ml), washed with water three times, dried and concentrated, the precipitated crystals were collected by filtration, and 6-(1-bromo-1-methyl)ethyl-4 -oxo-4H-1-benzopyran-3
- Colorless prism crystals (7.0 g) of carbonitrile were obtained. Melting point: 115°-117°C Reference example 2 6-(1-bromo-1-methyl)ethyl-4-
Oxo-4H-1-benzopyran-3-carbonitrile (9.6g) was added to 1N sodium hydroxide (250ml).
Dissolved in, stirred at room temperature for 2 hours, then cooled.
Acidified with concentrated hydrochloric acid. Ethyl acetate (200ml x 3)
After extracting with
The mixture was subjected to column chromatography and eluted with chloroform/acetone/formic acid (90:10:1).
After distilling off the solvent, ethanol was added to the residue, and after standing overnight, the precipitate was collected by filtration, and 6-(1-hydroxy-1-methyl)ethyl-4-oxo-4H
Crystals (436 g) of -1-benzopyran-3-carbonitrile were obtained. When this product was recrystallized from ethanol, it became colorless plate-like crystals. Melting point: 166°-167°C Reference example 3 6-(1-hydroxy-1-methyl)ethyl-
Piperidine (1.9 g) was added to 4-oxo-4H-1-benzopyran-3-carbonitrile (4.7 g), cyanacetic acid ethyl ester (2.5 g), and ethanol (100 ml), heated under reflux for 3 hours, and then cooled.
The precipitated crystals were collected by filtration. This was dissolved in chloroform, subjected to column chromatography on silica gel (120 g), and eluted with chloroform/acetone/formic acid (90:10:1). After distilling off the solvent, ethanol was added to the waste stream, the poorly soluble material was filtered out, recrystallized from chloroform, and ethyl 2-amino-7-
Colorless needle crystals (4.86 g) of (1-hydroxy-1-methyl)ethyl-5-oxo-5H-[1]benzopyrano[2,3-b]pyridine-3-carboxylate were obtained. Melting point: 236°-264°C Reference example 4 6-acetyl-4-oxo-4H-1-benzopyran-3-carbonitrile (32 g) was suspended in ethanol (800 ml), and ethyl cyanacetate (23.9
ml) and piperidine (23.7 ml) were added, heated under reflux for 1 hour, returned to room temperature, filtered the crystals, washed with ethanol and acetone, and dried to obtain ethyl 7-acetyl-2-amino-5. -Oxo-5H-[1]benzopyrano[2,3-b]pyridine-3-carboxylate yellow crystals (46.3g)
I got it. Melting point: >300°C Example 1 Ethyl 2-amino-7-(1-hydroxy-1
-Methyl)ethyl-5-oxo-5H-[1]benzopyrano[2,3-b]pyridine-3-carboxylate (37.3g), ethanol (2.3), 0.5N sodium hydroxide (620ml) suspension After stirring at 50°C for 2 hours, ethanol was distilled off. The concentrate was acidified with hydrochloric acid (PH3-4), the precipitate was collected by filtration, washed with water, recrystallized from dimethylformamide-water, and the obtained crystals were washed with ethanol to obtain 2-
Amino-7-(1-hydroxy-1-methyl)ethyl-5-oxo-5H-[1]benzopyrano[2,3-b]pyridine-3-carboxylic acid (32.5 g) was obtained. NMR (DMSO-d 6 ) ÎŽ: 1.53 (6H, s), 5.12
(1H, m), 7.50 (1H, d, J=9Hz), 7.92 (1H,
dd, J = 2and 9Hz), 8.20 (1H, d, J = 2Hz),
8.20 (2H, m), 8.85 (1H, s), 13.38 (1H, m) R Μ nujol nax cm -1 : 3450, 3320, 1680, 1665,
1610, 1535, 1230, 1220, 1160, 1120, 830, 790 Example 2 Ethyl 7-acetyl-2-amino-5-oxo-5H-[1]benzopyrano[2,3-b]pyridine-3-carboxylate (46 g) was suspended in ethanol (3), water (460 ml) and 1N sodium hydroxide (462 ml) were added, and the mixture was heated at room temperature for 1.5 hours, then 50
After stirring at -55°C for 2 hours, precipitated crystals were collected by filtration and washed with ethanol. Suspend the obtained crystals in warm water (approx. 2 ml) and add concentrated hydrochloric acid (20 ml).
Stir for 20 minutes, filter the hardly soluble materials, wash with water, recrystallize from dimethylformamide-water, and obtain 7-acetyl-2-amino-5-oxo-5H-[1]benzopyrano[2,3-b]pyridine- Colorless crystals (39.3 g) of 3-carboxylic acid were obtained. Melting point: >300°C Effects of the Invention The compound () of the present invention has an antiallergic effect and can be used for the prevention and treatment of asthma and the like.
Claims (1)
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ãã³é žèªå°äœãŸãã¯ãã®å¡©ã®è£œé æ³ã[Claims] 1 Represented by the general formula [Formula] [wherein R represents hydrogen or lower alkyl, and A represents [Formula] (R 1 represents hydrogen or lower alkyl) or -CO-, respectively] 2-amino-5-oxo-5H-[1]benzopyrano[2,3-b]pyridine-3-carboxylic acid derivative or a salt thereof. 2 Represented by the general formula [Formula] [In the formula, R represents hydrogen or lower alkyl, A represents [Formula] (R 1 represents hydrogen or lower alkyl) or -CO-, and R 2 represents lower alkyl] 2-Amino-5-oxo-5H-[1] represented by the general formula [Formula] (wherein R and A have the same meanings as above)
A method for producing a benzopyrano[2,3-b]pyridine-3-carboxylic acid derivative or a salt thereof.
Priority Applications (9)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP60015109A JPS61172880A (en) | 1985-01-28 | 1985-01-28 | 2-amino-5-oxo-5h-(1)benzopyrano(2,3-b)pyridine-3-carboxylic acid derivative and production thereof |
| KR1019860000323A KR920010047B1 (en) | 1985-01-28 | 1986-01-20 | Process for preparing 2-amino-5-oxo-5h-|1š benzopyrano |2,3-bš pyridine-3-carboxylic acid derivatives |
| CA000500151A CA1290758C (en) | 1985-01-28 | 1986-01-23 | 2-amino-5-oxo-5h-¬1|benzopyrano¬2,3-b|pyridine-3- carboxylic acid derivatives and their production |
| ES551201A ES8707537A1 (en) | 1985-01-28 | 1986-01-24 | 2-Amino-5-oxo-5H-[1]benzopyrano[2,3-b]pyridine-3-carboxylic acid derivatives and their production. |
| PT81913A PT81913B (en) | 1985-01-28 | 1986-01-27 | PROCESS FOR THE PREPARATION OF 2-AMINO-5-OXO-5H- (1) BENZOPYRANE, 3-B} -PYRIDINE-3-CARBOXYLIC ACID DERIVATIVES |
| AT86300502T ATE47594T1 (en) | 1985-01-28 | 1986-01-27 | 2-AMINO-5-OXO-5H(1>BENZOPYRANO(2,3B>PYRIDINCARBONS|UREDERIVATES AND THEIR PRODUCTION. |
| DE8686300502T DE3666589D1 (en) | 1985-01-28 | 1986-01-27 | 2-amino-5-oxo-5h-û1šbenzopyranoû2,3-bšpyridine-3-carboxylic acid derivatives and their production |
| EP86300502A EP0191568B1 (en) | 1985-01-28 | 1986-01-27 | 2-Amino-5-oxo-5H-[1]benzopyrano[2,3-b]pyridine-3-carboxylic acid derivatives and their production |
| US06/823,479 US4716167A (en) | 1985-01-28 | 1986-01-28 | 2-amino-5-oxo-5H-[1]benzopyrano[2,3-b]pyridine-3-carboxylic acid derivatives |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP60015109A JPS61172880A (en) | 1985-01-28 | 1985-01-28 | 2-amino-5-oxo-5h-(1)benzopyrano(2,3-b)pyridine-3-carboxylic acid derivative and production thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPS61172880A JPS61172880A (en) | 1986-08-04 |
| JPH0588236B2 true JPH0588236B2 (en) | 1993-12-21 |
Family
ID=11879663
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP60015109A Granted JPS61172880A (en) | 1985-01-28 | 1985-01-28 | 2-amino-5-oxo-5h-(1)benzopyrano(2,3-b)pyridine-3-carboxylic acid derivative and production thereof |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPS61172880A (en) |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS5083397A (en) * | 1973-11-28 | 1975-07-05 | ||
| JPS53111097A (en) * | 1977-03-08 | 1978-09-28 | Takeda Chem Ind Ltd | 1-azaxanthone derivative and its preparation |
| JPS53111096A (en) * | 1977-03-08 | 1978-09-28 | Takeda Chem Ind Ltd | 1-azaxanthone-3-carboxylic acid derivative and its preparation |
| JPS5448798A (en) * | 1977-09-26 | 1979-04-17 | Takeda Chem Ind Ltd | 3-tetrazolyl-1-azaxanthone derivative and its preparation |
| JPS59216888A (en) * | 1983-05-19 | 1984-12-06 | Takeda Chem Ind Ltd | 5-oxo-5h-(1)benzopyrano(2,3-b)pyridine derivative, its preparation and medicinal composition |
-
1985
- 1985-01-28 JP JP60015109A patent/JPS61172880A/en active Granted
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS5083397A (en) * | 1973-11-28 | 1975-07-05 | ||
| JPS53111097A (en) * | 1977-03-08 | 1978-09-28 | Takeda Chem Ind Ltd | 1-azaxanthone derivative and its preparation |
| JPS53111096A (en) * | 1977-03-08 | 1978-09-28 | Takeda Chem Ind Ltd | 1-azaxanthone-3-carboxylic acid derivative and its preparation |
| JPS5448798A (en) * | 1977-09-26 | 1979-04-17 | Takeda Chem Ind Ltd | 3-tetrazolyl-1-azaxanthone derivative and its preparation |
| JPS59216888A (en) * | 1983-05-19 | 1984-12-06 | Takeda Chem Ind Ltd | 5-oxo-5h-(1)benzopyrano(2,3-b)pyridine derivative, its preparation and medicinal composition |
Also Published As
| Publication number | Publication date |
|---|---|
| JPS61172880A (en) | 1986-08-04 |
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